title: Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia.
abstract: Recent studies demonstrated that autophagy is an important regulator of innate immune response. However, the mechanism by which autophagy regulates natural killer (NK) cell-mediated antitumor immune responses remains elusive. Here, we demonstrate that hypoxia impairs breast cancer cell susceptibility to NK-mediated lysis in vitro via the activation of autophagy. This impairment was not related to a defect in target cell recognition by NK cells but to the degradation of NK-derived granzyme B in autophagosomes of hypoxic cells. Inhibition of autophagy by targeting beclin1 (BECN1) restored granzyme B levels in hypoxic cells in vitro and induced tumor regression in vivo by facilitating NK-mediated tumor cell killing. Together, our data highlight autophagy as a mechanism underlying the resistance of hypoxic tumor cells to NK-mediated lysis. The work presented here provides a cutting-edge advance in our understanding of the mechanism by which hypoxia-induced autophagy impairs NK-mediated lysis in vitro and paves the way for the formulation of more effective NK cell-based antitumor therapies.
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Department of Oncology, and Laboratory of Immunogenetics and Allergology, Public Research Center for Health, L-1526 Luxembourg City, Luxembourg.
authors.forename: Joanna
authors.initials: J
authors.lastname: Baginska
authors.forename: Elodie
authors.initials: E
authors.lastname: Viry
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.forename: Aurélie
authors.initials: A
authors.lastname: Poli
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.forename: Kris
authors.initials: K
authors.lastname: van Moer
authors.forename: Sandrine
authors.initials: S
authors.lastname: Medves
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: Ing Swie
authors.initials: IS
authors.lastname: Goping
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001343:Autophagy / Q000276:immunology*; D000071186:Beclin-1; D015687:Cell Hypoxia / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D059008:Time-Lapse Imaging / Q000379:methods; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D053804:Granzymes
keywords: breast adenocarcinoma; hypoxic tumor microenvironment; immunotherapy; innate immunity